Cognitive decline is a hallmark of advanced age and neurodegenerative conditions such as Alzheimer's disease. The genetic factors underlying neurological impairment are poorly understood, and therapies to treat cognitive deficiencies, including the loss of long-term memory, are severely lacking. Caenorhabditis elegans will be used to identify genes involved in long-term associative memory in wild-type worms and an A2(1-42) expressing Alzheimer's disease model using a novel long-term associative memory (LTAM) assay. In AIM 1, Mos1-mediated transposon mutagenesis and a novel cDNA library based C. elegans overexpression strategy will be used to identify mutants with enhanced long-term memory. Candidate genes will be validated and characterized using RNAi, gene deletion strains, and promoter::GFP strains to delineate the temporal and functional properties of LTAM-relevant genes. Microarray analysis will also be used in AIM II to characterize the temporal changes in gene expression and transcript stability that correlate with the maintenance and extinction of long-term memory. Age-associated Alzheimer's disease remains an incurable and terminal degenerative disease. Our preliminary data suggest that C. elegans expressing neuronal A2(1-42) posses defects in long-term associative memory but not short-term memory or initial learning. In AIM III, the temporal appearance of various A2 species will be correlated with the loss of long-term memory. Moreover, transcriptional changes associated with loss of memory in A2 worms will be examined using microarrays. Known LTAM regulators, LTAM-related genes identified in AIM I, and pharmacological agents will be tested in A2 worms for factors that rescue the memory defect. Elucidation of novel genes and molecular pathways involved in formation and preservation of long-term memory may generate potent targets for therapeutic drug design.